Abstract OT3-27-01: Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: a multicenter, phase 2, umbrella, FUTURE trial
Authors: Zhi-Ming Shao, Zhong-Hua Wang, Yi-Zhou Jiang, Yin Liu, Xiu-Zhi Zhu, Yi Xiao, Song-Yang Wu, Wen-Jia Zuo, Qiang Yu, A-Yong Cao, Jun-Jie Li, Ke-Da Yu, Guang-Yu Liu, Jiong Wu, Tao Sun, Jiuwei Cui, Zheng Lv, Hui-Ping Li, Xiao-Yu Zhu
Journal: Cancer Research (2023)

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes (luminal androgen receptor [LAR], immunomodulatory [IM], basal-like immune-suppressed [BLIS], mesenchymal-like [MES]) with distinct molecular features. We aimed to assess the efficacy and safety of molecular subtype-derived precision treatment in patients with heavily pretreated metastatic TNBC. Methods: This open-label, phase 2, umbrella trial included patients from four centers in China. Participants were women (aged ≥18 years) with histologically confirmed metastatic TNBC with disease progression after multiple lines of standard chemotherapy. Patients were enrolled into seven parallel arms according to their molecular subtypes: LAR with or without ERBB2 somatic mutation/amplification assigned to arm A (pyrotinib with capecitabine) and arm B (androgen inhibitor included therapy); IM assigned to arm C (anti-PD-1 antibody with nab-paclitaxel); BLIS with or without BRCA1/2 germline mutation assigned to arms D (PARP inhibitor included therapy) and E (anti-VEGFR included therapy); MES without or with PI3K-AKT mutation assigned to arms F (anti-VEGFR included therapy) and G (everolimus with nab-paclitaxel). Bayesian predictive probability was adopted to monitor each arm, which can be terminated independently according to a prespecified futility or efficacy boundary. This trial is registered with ClinicalTrials.gov, NCT03805399. Findings: Between October 18, 2018, and February 11, 2022, we enrolled 141 patients. All patients were heavily pretreated and resistant to six categories of the most common chemotherapeutic agents used in breast cancer treatment, with a median of 3 previous lines of therapies in the metastatic setting (Table 1 and 2). The median follow-up was 18.3 months (IQR 11.7-27.7). A confirmed objective response was achieved in 42 (29.8%, 95% CI 22.4-38.1) of the 141 patients. The median PFS was 3.4 months (95% CI 2.7-4.2), and the median OS was 10.7 months (95% CI 9.0-12.3) (Table 3). Arms A, C, E and G achieved efficacy boundaries, with 3 (75.0%) out of 4 patients in arm A, 20 (43.5%) out of 46 patients in arm C, 13 (28.3%) out of 46 patients in arm E, and 3 (33.3%) out of 9 patients in arm G achieving objective responses. Potential predictive biomarkers of efficacy in each arm were explored. Safety data were consistent with the known safety profiles of relevant drugs. Interpretation: We demonstrate the feasibility and clinical utility of a subtyping-based, genomic sequencing-guided strategy which allows the majority of heavily pretreated metastatic TNBCs to benefit from precision treatment. Most arms exhibit promising efficacy and manageable toxicities, providing subtyping schema to optimize personalized treatment. Table 1. The FUTURE trial schema. Patients are stratified into seven arms using the FUSCC 484-gene NGS panel testing and IHC subtyping. Abbreviations: mTNBC, metastatic triple-negative breast cancer; NGS, next-generation sequencing; IHC, immunohistochemistry; FUSCC, Fudan University Shanghai Cancer Center; LAR, luminal androgen receptor; IM, immunomodulatory; BLIS, basal-like immune-suppressed; MES, mesenchymal-like; n, number; AR, androgen receptor; PD-1, programmed cell death-1; PARPi, poly ADP-ribose polymerase inhibitor; VEGF, vascular endothelial growth factor; mTORi, mammalian target of rapamycin inhibitors. Table 2. Patient characteristics in the FUTURE trial. Table 3. Summary of treatment efficacy of TNBC in the FUTURE trial Citation Format: Zhi-Ming Shao, Zhong-Hua Wang, Yi-Zhou Jiang, Yin Liu, Xiu-Zhi Zhu, Yi Xiao, Song-Yang Wu, Wen-Jia Zuo, Qiang Yu, A-Yong Cao, Jun-Jie Li, Ke-Da Yu, Guang-Yu Liu, Jiong Wu, Tao Sun, Jiuwei Cui, Zheng Lv, Hui-Ping Li, Xiao-Yu Zhu. Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: a multicenter, phase 2, umbrella, FUTURE trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-27-01.